NZ244458A

NZ244458A - Metal alkoxides of taxane derivatives

Info

Publication number: NZ244458A
Application number: NZ244458A
Authority: NZ
Inventors: Robert A Holton
Original assignee: Univ Florida State
Priority date: 1991-09-23
Filing date: 1992-09-23
Publication date: 1994-06-27
Also published as: HUT66398A; IL103192A; FI109796B; FI941323A0; FI941323A; MX9205370A; JP3320416B2; ATE184004T1; MY128481A; CZ66294A3; US5229526A; CZ289299B6; EP0605638B1; DE69229916T2; HU225914B1; PT100884A; CA2098568C; DK0605638T3; CN1058714C; PT100884B

Abstract

A metal alkoxide having the following formula: <IMAGE> (1) wherein T1 is hydrogen or a hydroxy protecting group, Z is -OT2, or -OCOCH3, T2 is hydrogen or a hydroxy protecting group, and M is selected from the group comprising Group IA, IIA and transition metals are useful in the preparation of biologically active derivatives of baccatin III and 10-deacetyl baccatin III.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £44458 2 4 4 4 5 8 Priority Date(s): .2,3*33^,.?;f+\^.. It No.: Date: Complete L'.on Filsd: Class: .conoid j* Publication Date: P.O. Journal, No: ....... /3W., NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION METAL ALKOXIDES We, FLORIDA STATE UNIVERSITY, a corporation of the State of Florida, United States of America, of 2035 East Paul Dirac Drive, Tallahassee, Florida 32310, United States of America hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) 244 458 - la - BACKGROUND OF THE INVENTION The present invention is directed to novel metal alkoxides useful in the preparation of derivatives of baccatin III and 10-deacetyl baccatin III such as taxol, 10 taxotere and other taxane derivatives which have biological activity. The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer 15 cheraotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has the following structure: OAc CfiHgCONH O . „ .. i u ;' 0H /V*J' v s / \ --**■ n C6H^ 1 ommifls CI) OH \ / "<11116/* 7 \ OH i H ^r\ s OAc\ --0 OCOCgHg 30 Because of this promising activity, taxol is currently 20 undergoing clinical trials in both France and the United States. The supply of taxol for these clinical trials is presently being provided by the bark from Taxus brevifolia 12 APR 1994 2 4 4 4 5 (Western Yew). However, taxol is found only in minute quantities in the bark of these slow growing evergreens, causing considerable concern that the limited supply of taxol will not meet the demand. Consequently, chemists in 5 recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxols. So Ear, the results have not been entirely satisfactory. One synthetic route that has been proposed is directed to the synthesis of the tetracyclic taxane nucleus 10 from commodity chemicals. A synthesis of the taxol congener taxusin has been reported by Holton, et al. in JACS 110. 6558 (1988). Despite the progress made in this approach, the final total synthesis of taxol is, nevertheless, likely to be a multi-step, tedious, and 15 costly process. An alternate approach to the preparation of taxol has been described by Greene, et al. in JACS 110, 5917 ( 1988), and involves the use of a congener of taxol, 10-deacetyl baccatin III which has the structure of formula 20 II shown below: HOtlMHI Cii) 10-deacetyl baccatin III is more readily available than taxol since it can be obtained from the needles of Taxus baccata. According to the method of Greene et al., 25 10-deacetyl baccatin III is converted to taxol by # 3 attachment of the C-10 acetyl group and by attachment of the C-13 B-amido ester side chain through the esterification of the C-13 alcohol with a B-amido carboxylic acid unit. Although this approach requires 5 relatively few steps, the synthesis of the B-amido carboxylic acid unit is a multi-step process which proceeds in low yield, and the coupling reaction is tedious and also proceeds in low yield. However, this coupling reaction is a key step which is required in every contemplated 10 synthesis of taxol or biologically active derivative of taxol, since it has been shown by Wani, et al. in JACS 93. 2325 (1971) that the presence of the B-amido ester side chain at C13 is required for anti-tumor activity. More recently, it has been reported in Colin et 15 al. U.S. Patent No. 4,814,470 that taxol derivatives of the formula III below, have an activity significantly greater than that of taxol (I). R' represents hydrogen or acetyl and one of R*' and R''' 20 represents hydroxy and the other represents tert-butoxy-carbonylamino and their stereoisomeric forms, and mixtures thereof. According to Colin et al., U.S. Patent 4,418,470, the products of general formula (III) are obtained by the 2 4 4 4 5 4 action of the sodium salt of tert-butyl N-chlorocarbamate on a product of general formula: J^l O Q OCOOCH2CI3 co-o J C0Hs in which R' denotes an acetyl or 2,2,2-trichloroethoxy-5 carbonyl radical, followed by the replacement of the 2,2,2-trichloroethoxycarbonyl group or groups by hydrogen. It is reported by Denis et al. in U.S. Patent No. 4,924,011, however, that this process leads to a mixture of isomers which has to be separated and, as a result, not all 10 the baccatin III or 10-deactylbaccatin III employed for the preparation of the product of general formula (IV) can be converted to a product of general formula (III). In an effort to improve upon the Colin et al. process, Denis et al. disclose a different process for 15 preparing derivatives of baccatin III or of 10-deactylbaccatin III of general formula Civ) OH ; H OCOCgHg OCOCH- 9 / / £ £ L \ 3 in which R' denotes hydrogen or acetyl wherein an acid of general formula: o—R, C vi) Cch3)3coconhv/ cooh in which R-^ is a hydroxy-protecting group, is condensed with a taxane derivative of general formula: ho -- OCOCH, OCOCgHg (VII) in which R2 is an acetyl hydroxy-protecting group and R3 is a hydroxy-protecting group, and the protecting groups R^, R3 and, where appropriate, R2 are then replaced by 10 hydrogen. However, this method employs relatively harsh conditions, proceeds with poor conversion, and provides less than optimal yields. A major difficulty remaining in the synthesis of taxol and other potential anti-tumor agents is the lack of 15 baccatin III and 10-deacetyl baccatin III derivatives which have been activated at the C-13 oxygen. Development of such derivatives would permit attachment of the B-amido ester side chain in high yield and thus, facilitate the synthesis of taxol as well as related anti-tumor agents 20 having a modified set of nuclear substituents or a modified C-13 side chain. •>' /' ■ -ft ■ "7 ; 'T 6 Another major difficulty encountered in the synthesis of taxol is that known processes for the attachment of the B-amido ester side chain at C-13 are generally not sufficiently diastereoselective. Therefore 5 the side chain precursor must be prepared in optically active form to obtain the desired diastereomer during attachment. SUMMARY OF THE INVENTION Among the objects of the present invention, 10 therefore, is the provision of activated baccatin III and 10-deacetyl baccatin III derivatives which permit attachment of the B-amido ester side chain in high yield, the provision of such derivatives which permit the use of a racemic mixture of side chain precursor, eliminating the 15 need for the expensive, time-consuming process of separating the precursor into its respective isomeric forms, and the provision of such derivatives which permit the preparation of taxanes having greater variety in the side-chain. 20 Briefly, therefore, the present invention is directed to a metal alkoxide having the formula: MOimiiii ot, (1) wherein T^ is hydrogen or a hydroxy protecting group, Z is -OT2, or -OCOCH3, T2 is hydrogen or a hydroxy 25 protecting group, and M is a metal, preferably, Li, Mg, Na, K or Ti. 2 4 4 4 5 8 7 Other objects and features of this invention will be in part apparent and in part pointed out hereinafter. DETAILED DESCRIPTION Metal alkoxides (1) are activated derivatives of 5 baccatin III and/or 10-deacetyl baccatin III and have particular utility in a process for the preparation of taxol, taxotere and other biologically active taxane derivatives. In accordance with the present invention, metal alkoxides (1) are reacted with G-lactam (2) to form a 10 G-amido ester intermediate. The intermediate is then converted to a biologically active taxane derivative. B-lactam (2) has the general formula: * '— 1 2 4 3 j C2) ^3 *2 wherein 15 Ri is -ORg, -SR7, or -NRgRg,* R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, 20 however, that R3 and R4 are not both acyl; R5 is —COR^g, -COOR^o, —COSR^g, —CONRgR-^g, -SO2R11t ~P0Ri2Ri3; R6 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group; 25 R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; 8 Rg is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; Rg is an amino protecting group; R10 is alkyl, alkenyl, alkynyl, aryl, or 5 heteroaryl; R^2. alkyl, alkenyl, alkynyl, aryl, heteroaryl, -ORiq/ or —NRgR^^; R22 an<3 Ri3 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10, or -NRgR14; and 10 R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl. In accordance with the present invention, R5 of 13-lactam (2) is preferably -COR^q with Rjq with R^q being aryl, p-substituted phenyl, or lower alkoxy, and most 15 preferably, phenyl, methoxy, ethoxy, tert-butoxy ("tBuO"; (CH3)3CO-) or wherein X is CI, Br, F, CH30-, or N02-. Preferably R2 and R4 are hydrogen or lower alkyl. R3 is preferably aryl, 20 most preferably, naphthyl, phenyl, f .? 9 'OMe Ph or wherein X is as previously defined, Me is methyl and Ph is phenyl. Preferably, is selected from -ORg, -SRy or 5 -NRgRg wherein Rg, R? and Rg, are hydroxy, sulfhydryl, and amine protecting groups, respectively, and Rg is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl. Most preferably, R^ is -ORg wherein Rg is triethylsilyl ("TES"), 1-ethoxyethyl ("EE") or 2,2,2-trichloroethoxymethyl. 10 The 13-lactam alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, 15 propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like. the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in 20 the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like. 25 the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be The 13-lactam alkenyl groups, either alone or with The 13-lactam alkynyl groups, either alone or with ^ f / / vT O / Li, I', is. " ; rl 10 straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like. The 13-lactam aryl moieties described, either alone or with various substituents, contain from 6 to 15 5 carbon atoms and include phenyl, a-naphthyl or fi-naphthyl, etc. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl. As noted above, R^ of 13-lactam (2) may be -ORg 10 with Rg being alkyl, acyl, ethoxyethyl ("EE"), triethylsilyl ("TES"), 2,2,2-trichloroethoxymethy1, or other hydroxyl protecting group such as acetals and ethers, i.e., methoxymethyl ("MOM"), benzyloxymethyl; esters, such as acetates; carbonates, such as methyl carbonates; and 15 alkyl and aryl silyl such as triethylsilyl, trimethylsilyl, dimethyl-t-butylsilyl, dimethylarylsilyl, dimethyl-heteroarylsilyl, and triisopropylsilyl, and the like. A variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in 20 Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981. The hydroxyl protecting group selected should be easily removed under conditions that are sufficiently mild, e.g., in 48% HF, acetonitrile, pyridine, or 0.5% HCl/water/ethanol, and/or zinc, acetic acid so as not to 25 disturb the ester linkage or other substituents of the taxol intermediate. Also as noted previously, Ry may be a sulfhydryl protecting group and Rg may be an amine protecting group. Sulfhydryl protecting groups include hemithioacetals such 30 as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates. Amine protecting groups include carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate. A variety of sulfhydryl and amine protecting groups may be found in the above-identified text 35 by T. W. Greene. m 4 H o 11 The 13-lactams (2) can be prepared from readily available materials, as is illustrated in schemes A and B below: Scheme A ci Ar OEE ch3o, OCH, Vf° Ar OEE cd Ar OAc b HW° ^ \ Ar OAc Scheme B A TESO OEt ArC HO H. rf ^—\ Ar 'OTES Ar OTES reagents: (a) triethylamine, CH2C12, 25°C, 18h; (b) 4 equiv eerie ammonium nitrate, CH3CN, -10°C, 10 min; (c) KOH, THF, H20, 0°C, 30 min; (d) ethyl vinyl ether, THF, toluene sulfonic acid (cat.), 0°C, 1.5h; (e) n-butyllithium, ether, 15 -78°C, 10 min; benzoyl chloride, -78°C, lh; (f) lithium 4 12 diisopropyl amide, THF -78°C to -50°C; (g) lithium hexamethyldisilazide, THF -78°C to 0°C; (h) THF, -78°C to 25 °C, 12h. The starting materials are readily available. In 5 scheme A, a-Acyloxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give l-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenyl group can be 10 readily removed through oxidation with eerie ammonium nitrate, and the acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones. The 3-hydroxyl group is protected with 1-ethoxyethyl, but may 15 be protected with variety of standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) silyl groups. In Scheme B, ethyl-a-triethylsilyloxyacetate is readily prepared from glycolic acid. The racemic fl-lactams may be resolved into the 20 pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reaction described hereinbelow in which the fi-amido ester side chain is attached has the advantage of being highly diastereo-25 selective, thus permitting the use of a racemic mixture of side chain precursor. The 3-(l-ethoxyethoxy)-4-phenylazetidin~2-one of Scheme A and the 3-(l-triethylsilyl)-4-phenylazetidin-2-one of Scheme B can be converted to B-lactam (2), by treatment 30 with a base, preferably n-butyllithium, and an acyl chloride, sulfonyl chloride, phosphinyl chloride, phosphoryl chloride or an alkyl chloroformate at -78°C or less. Preferably, the metal alkoxides are prepared by 35 reacting an alcohol having two to four rings of the taxane 2 4 4 4 13 nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent. Most preferably, the alcohol is a protected baccatin III, in particular, 7-0-triethylsilyl baccatin III (which can be obtained as 5 described by Greene, et al. in JACS 110. 5917 (1988) or by other routes) or 7,lO-bis-O-triethylsilyl baccatin III. As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-O-triethylsilyl-lO-deacetyl baccatin III according to the following reaction scheme: OCOCgHg (3) (4a) Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C2H5)3SiCl at 23°C under an argon 15 atmosphere for 20 hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-10-deacetyl baccatin III (4a) as a reaction product in 84-86% yield after purification. The reaction product (4a) is then acetylated with 20 5 equivalents of CH3COCI and 25 mL of pyridine/mmol of 4a at 0 °C under an argon atmosphere for 48 hours to provide 86% yield of 7-O-triethylsilyl baccatin III (4b) as reported by Greene, et al. in JACS 110. 5917 at 5918 (1988). Alternatively, 7-triethylsilyl-10-deacetyl 25 baccatin III (4a) can be protected at C-10 oxygen with an 24 4 4 5 14 acid labile hydroxyl protecting group. For example, treatment of (4a) with n-butyllithium in THF followed by triethylsilyl chloride (1.1 mol equiv.) at 0°C gives 7,10-bis-0-triethylsilyl baccatin III (4c) in 95% yield. Also, (4a) can be converted to 7-0-treithylsilyl-10-(l-ethoxyethyl) baccatin III (4d) in 90% yield by treatment with excess ethyl vinyl ether and a catalytic amount of methane sulfonic acid. These preparations are illustrated in the reaction scheme below. ococh3 OSiCC2H3)3 C4b) CjHJN OCOCH3 ococghg OSi(Cj Hg)3 n-BuLi OSlCC2Hg)3 4a HOHMiti (C2H5)3SiCl (4c) OCOCH3 OCOCgHg OEE 0SiCC2H5)3 CCAT)CH3S03H HO'iinn (4d) OCOCHg OCOCgHg 2 4 4 4 5 15 The 7-0-triethylsilyl baccatin III derivatives (4b, 4c or 4d) are reacted with an organometallic compound such as n-butyllithium in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-0-lithium-7-0-tri-5 ethylsilyl baccatin III derivative (5b, 5c or 5d) as shown in the following reaction scheme: z THF CH- CHaCHjCHjCHa + Lio-yj CH3 OSiCC2H5)3 OCOCqHJ (22b) Z = C22c) Z = C22d) Z = -OCOCH3 -OSiCCjHsDg -OEE 10 As shown in the following reaction scheme, the 13-0-lithium-7-0-triethylsilyl baccatin III derivative (5b, 5c, or 5d) reacts with 13-lactam (2) to provide an intermediate (6b, 6c, or 6d) in which the C-7 and C-2' hydroxyl groups are protected with a triethylsilyl group. 15 The triethylsilyl and ethoxyethyl groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane substituents. 16 2 4 4 4 z z ot. 5 b-d (2) 6 b-d b, Z = -OCOCH3 c/ Z = -OSi(C2Hj)j d, Z = -OEE 5 wherein is a hydroxy protecting group; M is a metal; Ph is phenyl; Ac is acetyl; and to R5 are as previously defined. 10 Group IA, IIA, IIIA, lanthanide or actinide element or a transition, Group IIIA, IVA, VA or VIA metal. Preferably, it is a Group IA, IIA or transition metal, and most preferably, it is lithium, magnesium, sodium, potassium or titanium. 15 Both the conversion of the alcohol to the metal alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel. Preferably, the B-lactam is added to the reaction vessel after formation therein of the metal alkoxide. 20 The organometallic compound n-butyllithium is preferably used to convert baccatin III or 10-deacetyl baccatin III to the corresponding metal alkoxide, but other sources of metallic substituent such as lithium diisopropyl amide, other lithium or magnesium amides, ethylmagnesium Metal substituent, M, of metal alkoxide (3) is a 17 bromide, methylmagnesium bromide, other organolithium compounds, other organomagnesium compounds, organosodium, organot itanium or organopotassium may also be used. Organometallic compounds are readily available, or may be 5 prepared by available methods including reduction of organic halides with metal. For example, butyl bromide can be reacted with lithium metal in diethyl ether to give a solution of n-butyllithium in the following manner: -10°C CH3CH2CH2CH2Br + 2 Li *> CH3CH2CH2CH2Li + LiBr ECjO 10 Although THF is the preferred solvent for the reaction mixture, other ethereal solvents, such as dimethoxyethane, or aromatic solvents may also be suitable. Certain solvents, including some halogenated solvents and some straight-chain hydrocarbons in which the 15 reactants are too poorly soluble, are not suitable. Other solvents are not appropriate for other reasons. For example, esters are not appropriate for use with certain organometallic compounds such as n-butyllithium due to incompatibility therewith. 20 Although the reaction scheme disclosed herein is ideally directed to the synthesis of taxol, taxotere, and other taxane derivatives exemplified herein, it can be used with modifications in either the 13-lactam or the tetracyclic metal alkoxide to produce other compounds. 25 Thus, the 13-lactam ana the tetracyclic metal alkoxide can be derived from natural or unnatural sources, to prepare other synthetic taxols, taxol derivatives, 10-deacetyl-taxols, and the enantiomers and diastereomers thereof contemplated within the present invention. 30 The process of the invention also has the important advantage of being highly diastereoselective. Therefore racemic mixtures of the side chain precursors may 24 4 4! 18 be used. Substantial cost savings may be realized because there is no need to resolve racemic G-lactams into their pure enantiomers. Additional cost savings may be realized because less side chain precursor, e.g., 60-70% less, is 5 required relative to prior processes. The following examples illustrate the invention. EXAMPLE 1 Preparation of 2•-ethoxyethyl-7-triethylsilyl taxol, and subsequently taxol, from racemic 13-lactam: 10 To a solution of 7-triethylsilyl baccatin III (20mg, 0.028 mmol) in 1 ml of THF at -78°C was added dropwise 0.17 ml of a 0.164M solution of nBuLi in hexane. After 30 min at -78°C, a solution of cis-l-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (47.5 mg, 0.14 15 mmol) in 1 ml of THF was added dropwise to the mixture. The solution was allowed to slowly warm (over 1.5 h) to 0°C and was then stirred at 0°C for 1 h and 1 ml of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 20 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by flash chromatography to give 23 mg (80%) of (2*R, 3'S)-2'-ethoxyethyl-7-triethylsilyl taxol and 3.5 mg (13%) of 2',3'-epi(2'S, 3'R)-2'-ethoxyethy1-7-triethylsilyl taxol. 25 A 5 mg sample of (2'R, 3'S)-2'-ethoxyethyl- 7-triethylsilyl taxol was dissolved in 2 ml of ethanol, and 0.5 ml of 0.5% aqueous HC1 solution was added. The mixture was stirred at 0°C for 30 h and diluted with 50 ml of ethyl acetate. The solution was extracted with 20 ml of 30 saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography to provide 4.5 mg (ca.90%) taxol, 2 4 4 4 19 which was identical with an authentic sample in all respects. A 5 mg sample of 2',3'-epi(2'S,3'R)-2'-ethoxy-ethyl-7-triethylsilyl taxol was dissolved in 2 ml of 5 ethanol and 0.5 ml of 0.5% aqueous HC1 solution was added. The mixture was stirred at 0°C for 30 h and diluted with 50 ml of ethyl acetate. The solution was extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was 10 purified by flash chromatography to provide 4.5 mg (ca.90%) of 2',3'-epitaxol. EXAMPLE 2 Preparation of 27-(bis)triethylsilyl taxol, and subsequently taxol, from racemic 13-lactam: 15 To a solution of 7-triethylsilyl baccatin III (lOOmg, 0.143 mmol) in 1 ml of THF at -45°C was added dropwise 0.087 ml of a 1.63M solution of nBuLi in hexane. After 1 h at -45°C, a solution of cis-l-benzoyl-3-triethylsilyloxy)-4-phenylazetidin-2-one (274 mg, 0.715 20 mmol) in 1 ml of THF was added dropwise to the mixture. The solution was allowed to warm to 0°C and held at 0°C for . 1 h. One ml of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the 25 organic layer gave a residue which was purified by flash chromatography followed by recrystallization to give 131 mg (85%) of (2'R, 3'S)-2',7-(bis)triethylsilyl taxol and 15 mg (10%) of 2',3'-epi(2'S,3'R)-2',7-(bis)triethylsilyl taxol. To a solution of 121.3 mg (0.112 mmol) of (2'R, 30 3'S)-2',7-(bis)triethylsilyl taxol in 6 ml of acetonitrile and 0.3 ml of pyridine at 0°C was added 0.9 ml of 48% aqueous HF. The mixture was stirred at 0°C for 8 h, then at 25°C for 6 h. The mixture was partitioned between 24 4 4 20 saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 113 mg of material which was purified by flash chromatography and recrystallization to give 94 mg (98%) taxol, which was 5 identical with an authentic sample in all respects. To a solution of 5 mg of (2'R, 3 'S)-2' , 7-(bis) triethylsilyl taxol in 0.5 ml of acetonitrile and 0.03 ml of pyridine at 0°C was added 0.09 ml of 48% aqueous HF. The mixture was stirred at 0°C for 8 h, then at 25°C for 6 10 h. The mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 5 mg of material which was purified by flash chromatography and recrystallization to give 4.6 mg (ca. 95%) of 2',3'-epitaxol. 24 4 4 5 21 EXAMPLE 3 Preparation of taxotere. To a solution of 7,10-bis-triethylsilyl baccatin III (200 mg, 0.248 mmol)) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 5C, a solution of cis-1-(tert-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (467 mg, 1.24 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 280 mg of crude 21,7,10-tris-triethylsilyl taxotere. « To a solution of 280 mg of the crude product obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 215 mg of material which was purified by flash chromatography to give 190 mg (95%) of taxotere, which was recrystallized from methanol/water. All analytical and spectral data were identical with that reported for taxotere in U. S. Patent 4,814,470. EXAMPLE 4 OAc o 24 4458 22 wherein Np2 is Preparation of 3 '-desphenyl-3'-(2-naphthyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-triethylsilyloxy-4-(2-naphthyl)azetidin-2-one (620 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of, a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(2-naphthyl) taxol and a small amount of the (2'S/3'R) isomer. To a solution of 320 mg (0.283 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatogr'|^hKv^.oN give ' * o\\ 24 4 4 5 8 23 166 mg (64%) of 3'-desphenyl-3'-(2-naphthyl) taxol, which was recrystallized from methanol/water. m.p. 164-165 °C;[a]25Na-52.6° (c 0.005, CHC13). 1H NMR (CDCI3, 300 MHz) S 8.14 (d, J = 7.3 Hz, 2H; benzoate ortho) , 7.96 (m, 1H, aromatic), 7.90 (m, 1H, aromatic), 7.85 (m, 2H, aromatic), 7.76 (m, 2H, aromatic), 7.60 (m, 3H, aromatic), 7.52 (m, 4H, aromatic), 7.41 (m, 2H, aromatic), 7.01 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.26 (dd, J = 9.2, 9.2 Hz, 1H, H13), 5.97 (dd, J = 8.8, 2.5 Hz, 1H, H3' ) , 5.68 (d, J = 7.1 Hz, 1H, H2I3) , 4.93 (m, 1H, H5), 4.92 (m, 1H, H2'), 4.39 (m, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H, H20a) , 4.20 (d, J = 8.5 Hz, 1H, H2013) , 3.81 (d, J = 7.1 Hz, 1H, H3), 3.60 (d, J - 5 Hz, 1H, 2'OH), 2.48 (m, 1H, H6a) , 2.45 (br, 1H, 70H) , 2.39 (s, 3H, 4Ac), 2.30 (m, 2H, H14) , 2.24 (s, 3H, lOAc) , 1.83 (m, 1H, H6G) , 1.82 (br s, 3H, Mel8), 1.68 (s, 1H, 10H), 1.68 (s, 3H, Mel9), 1.24 (s, 3H, Mel7), 1.14 (s, 3H, Mel6). 24 4 4 5E 24 wherein Np^ is no Preparation of 3'-desphenyl-3'-(1-naphthyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -4 5 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(l-naphthyl)azetidin-2-one (620 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 325 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(1-naphthyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 325 mg (0.287 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 260 mg of material which was purified by flash chromatography to give yjVr £'V > V C . 1 T-** i i ^ ^A';on J 24 4 4 58 25 166 mg (64%) of 3'-(1-naphthyl) taxol, which was recrystallized from methanol/water. m.p. 164-165 °C;[a]25Na-52.6° (c 0.005, CHC13). 1H NMR (CDCI3, 300 MHz) 5 8.11 (d, J = 7.1 Hz, 2H, benzoate ortho), 8.11 (m, 3H, aromatic), 7.91 (m, 3H, aromatic), 7.70 (m, 2H, aromatic), 7.63-7.46 (m, 7H, aromatic), 6.75 (d, J = 8.8 Hz, 1H, NH), 6.52 (dd, J = 8.8, 1.6 Hz, 1H, H3 ' ) , 6.27 (s, 1H, H10) , 6.27 (dd, J = 9.1, 9.1 Hz, 1H, H13) , 5.68 (d, J = 7.1 Hz, 1H, H2fi) , 4.85 (dd, J = 7.6, 2.2 Hz, 1H, H5) , .4.97 (dd, J = 1.6 Hz, 1H, H2'), 4.39 (m, 1H, H7) , 4.24 (d, J = 8.5 Hz, 1H, H20a) , 4.17 (d, J = 8.5 Hz, 1H, H20f3) , 3.80 (d, J = 7.1 Hz, 1H, H3) , 3.65 (br, 1H, 2'OH), 2.55 (m, 1H, H6a), 2.48 (br, 1H, 70H), 2.41 (s, 3H, 4 Ac) , 2.38 (m, 1H, H14) , 1.96 (s, 3H, lOAc), 1.86 (m, 1H, H6I3), 1.80 (br s, 3H, Mel8), 1.76 (s, 1H, 10H), 1.69 (s, 3H, Mel9), 1.28 (s, 3H, Mel7), 1.16 (s, 3H, Mel6). v O 24445ft 26 EXAMPLE 6 MbO OH Preparation of 3'-desphenyl-3'-(4-methoxyphenyl) taxol, To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (590 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-27-(bis)triethylsilyl-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.288 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred ^^for \ r O \ •C' \\ ' J/} kt. Of '\ •N ' V * o 24 4 27 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatography to give 172 mg (68%) of 3'-desphenyl-3'-(4-methoxyphenyl) taxol, which was recrystallized from methanol/water. m.p. 174-176 °C;[a]25Na-48.86° (c 0.05, CHC13). 1H NMR (CDCI3, 300 MHz) S 8.12 (d, J = 7.1 Hz, 2H, benzoate ortho) , 7.72 (m, 2H, aromatic), 7.59 (m, 1H, aromatic), 7.53-7.36 (m, 8H, aromatic), 6.96 (d, J ~ 8.8 Hz, 1H, NH), 6.90 (m, 2H, aromatic), 6.26 (s, 1H, H10) , 6.21 (dd, J = 9.3, 9.3 Hz, 1H, H13) , 5.70 (dd, J = 8.8, 2.7 Hz, 1H, H3 •) , 5.66 (d, J = 6.8 Hz, 1H, H2I3) , 4.93 (dd, J = 9.9, 2.2 Hz, 1H, H5) , 4.74 (dd, J = 5.5, 2.7 Hz, 1H, H2' ) , 4.39 (m, 1H, H7) , 4.29 (d, J = 8.8 Hz, 1H, H20a) , 4.18 (d, J = 8.8 Hz, 1H, H20G), 3.78 (d, J = 6.8 Hz, 1H, H3), 3.78 (s, 3H, ArOMe) . 3.67 (d, J = 5.5 Hz, 1H, 2'OH), 2.61 (m, 1H, H6a) , 2.50 (d, J = 4.4 Hz, 1H, 70H) , 2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14) , 2.22 (s, 3H, lOAc) , 1.84 (m, 1H, H6B) , 1.79 (br s, 3H, Mel8), 1.79 (s, 1H, IOH) , 1.67 (s, 3H, Mel9), 1.22 (s, 3H, Mel7), 1.13 (s, 3H, Mel6). ■v 24 4458 28 EXAMPLE 7 CI OH Preparation of 3'-desphenyl-3'-(4-chlorophenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 inL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(4-chlorophenyl)azetidin-2-one (595 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-2*,7-(bis)triethylsilyl 3'-desphenyl-3'-(4-chlorophenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.287 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred>\a£.:4K °C for : * \\ 1a ■ '■ Of! ^ ">1992 *j} 24 44 58 29 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatography to give 158 mg (62%) of 3'-desphenyl-3'-(4-chlorophenyl) taxol, which was recrystallized from methanol/water. m .p. 173-175 °C;[a]25Na-50.8° (c 0.01, CHCI3) 1H NMR (CDCI3, 300 MHz) S 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.72 (d, J = 8.2 Hz, 2H, benzamide ortho), 7.65-7.35 (m, 10H, aromatic), 6.97 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10) , 6.25 (dd, J = 8.3, 8.3 Hz, 1H, H13), 5.78 (dd, J = 8.8, 2.2 Hz, 1H, H3') , 5.67 (d, J = 7.1 Hz, 1H, H2I3) , 4.95 (dd, J = 8.8, 2.2 Hz, 1H, H5) , 4.77 (br s, 1H, H2'), 4.40 (m, 1H, H7), 4.31 (d, J = 8.2 Hz, 1H, H20a), 4.19 (d, J = 8.2 Hz, 1H, H20I3) , 3.80 (d, J = 7.1 Hz, 1H, H3), 3.61 (br s, 1H, 2*OH), 2.54 (m, 1H, H6a), 2.38 (s, 3H, 4Ac), 2.32 (m, 2H, H14), 2.24 (s, 3H, lOAc), 1.85 (m, 1H, H6fi), 1.80 (br s, 3H, Mel8) , 1.68 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6). 24 4458 Preparation of 3'-desphenyl-3'-(4-bromophenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution in nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(4-bromophenyl) azetidin-2-one (660 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of a mixture containing (2'R,3'S)-2' ,7-(bis)triethylsilyl-3'-desphenyl-3'-(4-bromophenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 330 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred afcr-JO. °C for 3 h, then at 25 °C for 13 h, and partitioned ^e"t'ft&en 24 44 58 31 saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 265 mg of material which was purified by flash chromatography to give 186 mg (64%) of 3'-desphenyl-3'-(4-bromophenyl) taxol, which was recrystallized from methanol/water. m.p. 170-172 °C;[a]25Na-50.94° (c 0.01, CHCI3). ■^H NMR (CDCI3, 300 MHz) S 8.12 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.71 (m, 2H, aromatic), 7.61 (m, 1H, aromatic), 7.50-7.47 (m, 6H, aromatic), 7.38 (m, 3H, aromatic), 7.04 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.23 (dd, J = 8.2, 8.2 Hz, 1H, H13), 5.75 (dd, J = 8.8, 2.2 Hz, 1H, H31), 5.66 (d, J » 7.1 Hz, 1H, H2fl), 4.94 (dd, J = 9.3, 1.7 Hz, 1H, H5), 4.75 (dd, J = 2.2 Hz, 1H, H2•), 4.38 (m, 1H, H7), 4.29 (d, J = 8.2 Hz, 1H, H20a) , 4.18 (d, J = 8.2 Hz, 1H, H20I3), 3.79 (d, J = 7.1 Hz, 1H, H3), 3.7 (br, 1H, 2'OH), 2.53 (m, 1H, H6a), 2.38 (br, 1H, 70H), 2.37 (s, 3H, 4Ac) , 2.30 (m, 2H, H14) , 2.23 (s, 3H, 10Ac), 1.87 (m, 1H, H6I3) , 1.80 (br s, 3H, Mel8), 1.80 (s, 1H, IOH), 1.67 (s, 3H, Mel9), 1.22 (s, 3H, Mel7), 1.13 (s, 3H, Mel6). £ /V •••V c\ » «1,\ V (I 1 $ J A «, c)l \. 'A ' ' . '** 1 \> r O, -• 2 4 4 4 5 8 32 EXAMPLE 9 OH Preparation of 3'-desphenyl-3'-(3,4-methylene-dioxyphenyl) taxol. To a solution of 7-triethyTsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(3,4-methylenedioxyphenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2 ' R, 3'S)-2',7-(bis)triethylsilyl-3 ' -desphenyl-3'-(3,4-methylenedioxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C wasfa^ed 2.8 ,y A 24 44 58 33 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 113 mg of material which was purified by flash chromatography to give 165 mg (64%) of 3-desphenyl-3'-(3,4-methylenedioxyphenyl) taxol, which was recrystallized from methanol/water. m .p. 178-180 °C; [<x]25Na-46.6° (c 0.005, CHCI3) 1H NMR (CDCI3, 300 MHz) S 8.14 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.72 (m, 2H, aromatic), 7.15 (m, 1H, aromatic), 7.50 (m, 2H, aromatic), 7.38 (m,2H, aromatic), 7.0 (m, 1H, aromatic), 6.94 (m, 2H, aromatic), 6.88 (d, J = 9.1 Hz, 1H, NH), 6.83 (m, 1H, aromatic), 6.28 (s, 1H, H10), 6.23 (dd, J = 9.1, 9.1 Hz, 1H, H13), 5.97 (s, 2H, methylene), 5 . o9 (dd, J = 9.1, 2.5 Hz, 1H, H3' ) , 5.68 (d, J « 6.9 Hz, 1H, H2I3) , 4.95 (dd, J = 9.6, 2.2 Hz, 1H, H5), 4.72 (dd, J = 2.5 Hz, 1H, H2'), 4.41 (m, 1H, H7), 4.31 (d, J = 8.4 Hz, 1H, H20a), 4.20 (d, J = 8.4 Hz, 1H, H20B), 3.81 (d, J = 6.9 Hz, 1H, H3), 3.60 (br, 1H, 2'OH), 2.56 (m, 1H, H6a), 2.43 (d, J = 4.1 Hz, 1H, 70H) , 2.39 (s, 3H, 4Ac) , 2.31 (m, 2H, H14), 2.24 (s, 3H, lOAc), 1.88 (m, 1H, H6IB) , 1.82 (br s, 3H, Mel8), 1.69 (S, 1H, 10H) , 1.68 (s, 3H, Mel9), 1.24 (s, 3H, Mel7), 1.15 (s, 3H, Mel6). .•/" ^ o <<•> \, .**3 _ — ' 1 ; r » 24 44 58 34 OH Preparation of 3'-desphenyl-3'-(3,4-dimethoxy-phenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(3,4-dimethoxyphenyl)azetidin-2-one (630 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 hr before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3 desphenyl-3'-(3,4-dimethoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 330 mg (0.286 mmol) of the mixture obtained from the previous reaction in. .18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C. gist's a&ded 2.8 '' .■'•V ' > : £ fv c 24 4458 35 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 260 mg of material which was purified by flash chromatography to give 175 mg (67%) of 3 *-desphenyl-3'-(3,4-dimethoxyphenyl) taxol, which was recrystallized from methanol/water. m .p. 165-167 °C; [cxJ25Na-42.0o (c 0.005, CHC13) . XH NMR (CDC13, 300 MHz) S 8.12 (d, J = 8.3 Hz, 2H, benzoate ortho), 7.73 (d, J = 8.2 Hz, 2H, benzamide ortho), 7.65-7.35 (m, 6H, aromatic), 7.1-7.0 (m, 2H, aromatic), 6.94 (d, J = 8.8 Hz, 1H, NH) , 6.88 (d, J = 8.3 Hz, 2H, aromatic), 6.27 (s, 1H, H10), 6.21 (dd, J = 9.3, 9.3 Hz, lh, H13) , 5.69 (m, 2H, H3, H2IB) , 4.94 (dd, Hz, J = 9.9, 2.2 Hz, 1H, H5), 4.77 (d, J = 2.8 Hz, 1H, H21 ) , 4.39 (dd, J = 11.0, 6.6 Hz, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H, H20a), 4.19 (d, J = 8.5 Hz, 1H, H20I3), 3.88 (s, 3H, ArOtle) , 3.87 (s, 3H, ArOMe), 3.80 (d, J = 7.1 Hz, 1H, H3), 3.59 (d, J = 4.4 Hz, 1H, 2'OH), 2.54 (m, 1H, H6a), 2.38 (s, 3H, 4Ac), 2.36 (m, 2H, H14a, H14I3) , 2.23 (s, 3H, lOAc) , 1.86 (m, 1H, H6B) , 1.80 (br s, 3H, Mel8), 1.68 (s, 3H, Mel9) , 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6). 24 4 4 5 0i 36 EXAMPLE 11 O Ph O OAc AAA /= EtO N oiiii'"' H OH OH Preparation of N-debenzoyl-N-ethoxycarbonyl taxol. To a solution of 7-triethylsilyl baccatin III (155 mg, 0.221 mmol) in 2 mL of THF at -45 °C was added dropwise 0.136 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-ethoxycarbonyl-3-triethylsilyloxy-4-phenylazetidin-2-one (386 mg, 1.11 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 252 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-ethoxycarbonyl taxol and a small amount of the (2'S,3'R) isomer. To a solution of 252 mg (0.112 mmol) of the mixture obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between 7 ' >\ 18 J'^l993 £/ A • J s,-.p;v£. 24 4 4 58 37 saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 216 mg of material which was purified by flash chromatography to give 155 mg (85%) of N-debenzoyl-N-ethoxycarbonyl taxol, which was recrystallized from methanol/water. m.p. 161.5-162.5 °C; [a]25Na-62 .2° (c 0.51, CHCI3) . ifi NMR (CDC13, 300 MHz) S 8.12 (d, J = 7.7 Hz, 2H, benzoate ortho), 7.65-7.3 (m, 8H, aromatic), 6.28 (m, 1H, H10) 6.27(m, 1H, H13) , 5.67 (d, J = 7.1 Hz, 1H, H2I3), 5.53 (d, J = 9.3 Hz, 1H, H3'), 5.29 (d, J = 9.3 Hz, 1H, NH), 4.94 (dd, J = 9.3, 2.2 Hz, 1H, H5) , 4.64 (dd, J = 5.0, 2.8 Hz, 1H, H2' ) , 4.41 (m, 1H, H7), 4.29 (d, J = 8.5 Hz, 1H, H20a), 4.17 (d, J = 8.5 Hz, 1H, H20B) , 4.01 (q, J = 7.1 Hz, 2H, COO£H2CH3), 3.79 (d, J = 7.1 Hz, 1H, H3), 3.45 (d, J = 5 Hz, 1H, 2'OH) , 2.54 (m, 1H, H6a) , 2.47 (d, J = 3.9 Hz 1H, 70H) , 2.36 (s, 3H, 4Ac),2.24 (s, 3H, lOAc) , 2.22 (m, 2H, H14a, H14B), 1.87 (m, 1H, H6a), 1.83 (br s, 3H, Mel8), 1.77 (s, 1H, 10H), 1.68 (s, 3H, Mel9), 1.27 (s, 3H, Mel7) , 1.15 (s, 3H, Mel6), 1.14 (t, J = 7.1 Hz, 2H, COOCH2£H3) . . ' x O -\ i;M t *V> \\ 24 4 4 38 EXAMPLE 12 Preparation of 3'-desphenyl-3*-(4-nitrophenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(4-nitrophenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-2 ' ,7-(bis)triethylsilyl-3'-desphenyl-3'-(4-nitrophenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixtur^was" 's£rirred at 0 °C for Ojj f 8 J A N tianv uyj o : • r t M o sy*' a // 14 4458 39 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatography to give 147 mg (57%) of 3'-desphenyl-3'-(4-nitrophenyl) taxol, which was recrystallized from methanol/water. m.p. 188-190 °C; [<x]25Na-63.7° (c 0.01, CHC13) . 1H NMR (CDC13, 300 MHz) 5 8.26 (d, J = 8.8 Hz, 2H, benzoate ortho), 8.20 (m, 2H, aromatic), 7.73 (m, 4H, aromatic), 7.60 (m, 1H, aromatic), 7.52 (m, 4H, aromatic), 7.41 (m, 1H, aromatic), 7.15 (d, J = 8.8 Hz, 1H, NH), 6.26 (s, 1H, H10) , 6.26 (dd, J = 9.3, 9.3 Hz, 1H, H13), 5.93 (dd, J = 8.8, 2.8 Hz, 1H, H3') , 5.66 (d, J = 6.6 Hz, 1H, H2I3), 4.94 (dd, J = 9.3, 1.7 Hz, 1H, H5), 4.82 (dd, J = 3.9, 2.8 Hz, 1H, H2'), 4.38 (m, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20a), 4.19 (d, J = 8.8 Hz, 1H, H20I3) , 3.86 (d, J = 3.9 Hz, 1H, 2 ' OH) , 3.79 (d, J = 6.6 Hz, 1H, H3), 2.55 (m, 1H, H6a), 2.46 (d, J = 3.8 Hz, 1H, 70H), 2.41 (s, 3H, 4Ac) , 2.38 (m, 2H, H14) , 2.23 (s, 3H, lOAc) , 1.82 (m, 1H, H6B) , 1.80 (br s, 3H, Mel8), 1.74 (s, 1H, 10H) , 1.68 (s, 3H, Mel9), 1.21 (s, 3H, Me17), 1.13 (s, 3H, Mel6). 40 EXAMPLE 13 24 44 58 o o OAc XXX x N =■ O'iniik Ph N H OH C4) Preparation of N-debenzoyl-N-methoxycarbonyl taxol. To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1 mL of THF at - 45°C was added dropwise 0.087 mL of a 163M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-methoxycarbonyl-3-triethylsilyloxy-4-phenylazetidin-2-one (252 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between • saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 129 mg of a mixture containing (2 *R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-methoxycarbonyl taxol and a small amount of the (2'S,3'R) isomer. To a solution of 129 mg (0.112 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 rXd--was added 0.9 \ 8 jA^i99^ £f // 4 4 4 5 8; 41 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 108 mg of material which was purified by flash chromatography to give 90 mg (76%) of N-debenzoyl-N-methoxycarbonyl taxol, which was recrystallized from methanol/water. m .p. 169-171 °C; [a]25Na-63.7° (c 1.1, CHC13). 1H NMR (CDC13, 300 MHz) S 8.12 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.65-7.3 (m, 8H, aromatic), 6.28 (m, 2H, H10, H13), 5.66 (d, J = 7.1 Hz, 1H, H213) , 5.58 (d, J = 9.4 Hz, 1H, H3'), 5.30 (d, J = 9.4 Hz, 1H, NH), 4.93 (dd, J = 9.3, 1.7 Hz, 1H, H5), 4.65 (br s, 1H, H2'), 4.40 (m, 1H, H7), 4.29 (d, J = 8.8 Hz, 1H, H20a) , 4.17 (d, J = 8.8 Hz, 1H, H20I3) , 3.79 (d, J = 7.1 Hz, 1H, H3), 3.58 (s, 3H, COOMfi), 3.34 (d, J = 5 Hz, 1H, 2'OH), 2.54 (m, 1H, H6a), 2.47 (d, J = 3.8 Hz 1H, 7 OH) , 2.36 (s, 3H, 4Ac),2.24 (s, 3H, lOAc) , 2.22 (m, 2H, H14a, H1413) , 1.88 (m, 1H, H6a) , 1.82 (br s, 3H, Mel8) , 1.73 (s, 1H, IOH), 1.68 (s, 3H, Mel9), 1.27 (s, 3H, Mel7), 1.14 (s, 3H, Mel6). % o , t, f +C •\ 18 y , f? r + f 24 4 4 58 42 EXAMPLE 14 Preparation of 3'-desphenyl-3(4-fluorophenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-tri-ethylsilyloxy-4-(4-fluorophenyl)azetidin-2-one (570 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 315 mg of a mixture containing (2*R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 315 mg (0.286 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C.was added 2.8 O v / J . g A T'/J // •tj „ O />v ' •r * v 4 4458 43 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 250 mg of material which was purified by flash chromatography to give 160 mg (64%) of 3'-desphenyl-3'-(4-fluorophenyl) taxol, which was recrystallized from methanol/water. m.p.171-173 °C;[a]25Na-49.0° (c 0.005, CHCI3). 1H NMR (CDCI3, 300 MHz) 6 8.13 (d, J = 7.5 Hz, 2H, benzoate ortho), 7.25 (m, 2H, aromatic), 7.61 (m, 1H, aromatic), 7.50 (m, 4H, aromatic), 7.43 (m, 2H, aromatic), 7.10 (m, 2H, aromatic), 6.96 (d, J = 8.7 Hz, 1H, NH), 6.27 (s, 1H, H10) , 6.25 (dd, J = 8.7, 8.7 Hz, 1H, H13), 5.79 (dd, J = 8.7, 2.4 Hz, 1H, H3 ' ) , 5.67 (d, J = 7.1 Hz, 1H, H2I3) , 4.45 (dd, J = 7.9 Hz, 1H, H5), 4.76 (dd, J = 4.8, 2.4 Hz, 1H, H21 ) , 4.39 (m, 1H, H7) , 4.31 (d, J = 8.9 Hz, 1H, H20a) , 4.20 (d, J = 8.9 Hz, 1H, H20I3), 3.80 (d, J = 7.1 Hz, 1H, H3), 3.57 (d, J = 4.8 Hz, 1H, 2'OH), 2.58 (m, 1H, H6a) , 2.43 (d, J = 4.3 Hz, 1H, 70H), 2.38 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.24 (s, 3H, lOAc), 1.85 (m, 1H, H6I3), 1.80 (br s, 3H, Mel8), 1.69 (s, 1H, 10H) , 1.55 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6). *0 \ f \V 1 o ' •\ ?•/ 44 EXAMPLE 15 4 4 4 58' o ^ o OAC I § H OH C5) Preparation of 3'-Desphenyl-3(2-thienyl) taxol. To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.087 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-(4-benzoyl)-3-triethylsilyloxy-4-(2-thienyl)azetidin-2-one (277 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCC>3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 169 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(2-thienyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 169 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48% aqueous HF. I • 13 jAKI99$ ^ - // </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 24 4 4 58: 45 The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 140 mg of material which was purified by flash chromatography to give 93 mg (76%) of 3'-desphenyl-3'-(2-thienyl) taxol, which was recrystallized from methanol/water. m .p. 173-175 °C; [<x]25Na-42 .1° (c 0.515, CHCI3) . 1H NMR (CDC13, 300 MHz) S 8.14 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.72 (d, J = 8.7 Hz, 2H, benzamide ortho), 7.65-7.35 (m, 6H, aromatic), 7.31 (dd, J = 5.5, 1.1 Hz, 1H, thienyl), 7.19 (dd, J =3.9, 1.1 Hz, 1H, thienyl), 7.03 (dd, J = 5.5, 3.9 Hz, 1H, thienyl), 6.96 (d, J = 8.8 Hz, 1H, NH), 6.28 (s, 1H, H10) , 6.24 (dd, J = 8.8, 7.7 Hz, 1H, H13), 6.05 (dd, J = 8.8, 1.7 Hz, 1H, H3'), 5.68 (d, J = 7.1 Hz, 1H, H2), 4.95 (dd, J = 9.3, 1.7 Hz, 1H, H5), 4.78 (d, J = 2.2 Hz, 1H, H2' ) , 4.40 (dd, J = 11.0, 6.6 Hz, 1H, H7) , 4.31 (d, J = 8.5 Hz, 1H, H20a) , 4.20 (d, J = 8.5 Hz, 1H, H20I3), 3.81 (d, J = 7.1 Hz, 1H, H3), 3.72 (br. s, 1H, 2'OH), 2.54 (m, 1H, H6a), 2.41 (s, 3H, 4Ac), 2.37 (m, 2H, H14a, H14B) , 2.23 (s, 3H, lOAc) , 1.88 (m, 1H, H6a) , 1.82 (br s, 3H, Mel8), 1.68 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6). In view of the above, it will be seen that the several objects of the invention are achieved. As various changes could be made in the above compositions and processes without departing from the scope of the invention, it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense. „ ^ / OI} 244458 46 WHAT ^/WE CLAIM IS a

1. A metal alkoxide having the following formula: z wherein is hydrogen or a hydroxy protecting group, Z is -0T2, or -OCOCH3, T2 is hydrogen or a hydroxy protecting group, M is a metal, Ac is acetyl and Ph is phenyl.

2. The metal alkoxide of claim 1 wherein M is Li, Mg, Na, K or Ti.

3. The metal alkoxide of claim 1 wherein M is lithium.

4. The metal alkoxide of claim 1 wherein M is lithium, Z is -OT2, and T2 is a hydroxy protecting group.

5. The metal alkoxide of claim 4 wherein Tj and T2 are independently selected from the group consisting of 1-ethoxyethyl, 2,2,2-trichloroethoxymethyl, trialkyl silyl and triaryl silyl.

6. A metal alkoxide according to any one of claims 1 to 5 </div>